Highlights
• Long-term (median 33.6 months) follow-up of the randomized phase III DeFi trial confirms durable benefit with continuous nirogacestat in adults with progressive desmoid tumors: median PFS remained unreached and objective response rate was 45.7% (32/70).
• Additional tumor responses accrued since the primary analysis (three further partial responses and three further complete responses) and most patients experienced continued target lesion shrinkage.
• Patient-reported outcome improvements were sustained on treatment and treatment-emergent adverse events (TEAEs) decreased in incidence and severity over time; only four patients discontinued for TEAEs between years 2 and 4.
Background: Clinical Context and Unmet Need
Desmoid tumors (also called desmoid-type fibromatosis) are rare, clonal, non-metastasizing soft-tissue neoplasms characterized by locally aggressive growth and a variable clinical course. They can produce substantial morbidity because of pain, impaired function, and local invasion of vital structures. Management paradigms have evolved from routine surgery to more conservative strategies that include active surveillance, local therapies, and systemic treatment selectively for symptomatic or progressive disease.
Systemic therapies for progressive desmoid tumors have included hormonal agents, nonsteroidal anti-inflammatory drugs, conventional cytotoxic chemotherapy, and targeted tyrosine kinase inhibitors; responses and tolerability vary and long-term disease control remains an important unmet need for many patients. Nirogacestat, an oral gamma-secretase inhibitor, targets a pathway relevant to desmoid biology and has shown promise in earlier analyses of the DeFi randomized, placebo-controlled phase III study (ClinicalTrials.gov NCT03785964).
Study Design and Methods
The DeFi trial is a randomized, placebo-controlled phase III trial in adults with progressing desmoid tumors. The prespecified primary analysis demonstrated clinically meaningful improvements with nirogacestat versus placebo across progression-free survival (PFS), objective response rate (ORR by RECIST v1.1), and patient-reported outcomes (PROs). The present report describes long-term outcomes for patients randomized to nirogacestat and followed through the final data cutoff on December 19, 2024, with a median (range) exposure of 33.6 (0.3–61.8) months.
Key prespecified endpoints evaluated in the long-term analysis included PFS and ORR per RECIST v1.1, sustained PRO measures, and safety (treatment-emergent adverse events and discontinuations). The presented efficacy and safety summaries reflect continued on-study follow-up beyond the primary analysis interval.
Key Findings
Durability of Disease Control and Objective Responses
During extended follow-up (median exposure 33.6 months), median PFS for the nirogacestat-treated cohort remained unreached. The ORR with up to 4 years of continuous nirogacestat treatment was 45.7% (32 of 70 patients), reflecting further activity beyond the primary analysis. Since the primary analysis, three additional partial responses and three additional complete responses were recorded. The report highlights that most patients experienced further reductions in target tumor size over time, indicating not only response durability but continued on-treatment tumor regression in a substantial subset.
Patient-Reported Outcomes
Patient-reported outcome benefits observed in the primary analysis were sustained during long-term treatment. Although the report does not detail the specific instruments or magnitude of change in this summary, the sustained PRO benefit is clinically meaningful in desmoid disease, where pain control, physical function, and quality of life are critical outcome domains for patients and clinicians making treatment decisions.
Safety and Tolerability Over Time
Treatment-emergent adverse events were commonly observed early but decreased in both incidence and severity with continued exposure. Importantly, only four patients discontinued nirogacestat because of TEAEs between years 2 and 4 of follow-up, suggesting an improving tolerability profile with prolonged therapy in most patients. The long-term safety profile was described as consistent with the primary analysis.
Clinical Interpretation of Effect Sizes and Course
The ORR of 45.7% at up to 4 years positions nirogacestat as an active oral option for patients with progressive desmoid tumors, with durable disease control (median PFS not reached) and ongoing tumor shrinkage in many responders. The accrual of additional partial and complete responses with extended exposure suggests that continued therapy can convert partial regressions into complete responses in a minority of patients and that some radiographic benefits evolve over prolonged treatment intervals.
Expert Commentary and Contextualization
Mechanistically, nirogacestat inhibits gamma-secretase, modulating Notch signaling and downstream processes implicated in desmoid tumor biology. Although desmoid tumors are most commonly driven by alterations in the Wnt/β-catenin pathway (CTNNB1 mutations) or the APC gene in familial adenomatous polyposis, cross-talk between signaling pathways likely contributes to tumor growth and presents opportunities for therapeutic intervention beyond direct Wnt targeting.
From a clinical standpoint, the DeFi long-term data strengthen the case for nirogacestat as a disease-modifying systemic therapy in patients with symptomatic or progressive desmoid tumors who require intervention. The combination of a high and durable ORR, progressive tumor shrinkage over time, and sustained PRO improvement addresses both objective disease control and patient-centered outcomes.
Comparative Considerations
Decisions about systemic therapy for desmoid tumors are individualized and consider disease location, symptom burden, prior therapies, and patient preference. Nirogacestat adds to the therapeutic armamentarium alongside TKIs and other systemic agents; its oral administration and demonstrated long-term activity are attractive attributes. Direct head-to-head comparisons are not available, so cross-trial comparisons should be made cautiously.
Safety Considerations and Reproductive Health
Gamma-secretase inhibitors as a class have been associated with a spectrum of adverse events that warrant focused monitoring, including gastrointestinal effects, rash, and effects on ovarian function and menstrual cycles described in earlier reports. The long-term DeFi findings indicate that TEAEs tend to lessen in incidence and severity with ongoing treatment, but clinicians should remain vigilant about reproductive and endocrine effects, counsel patients of childbearing potential, and consider fertility preservation discussions where appropriate. The trial report noted only four discontinuations for TEAEs between years 2 and 4, which is reassuring but does not obviate the need for individualized risk–benefit discussions.
Limitations and Unanswered Questions
The long-term analysis presents valuable extended follow-up, but several important questions remain. First, the median PFS remains unreached; longer follow-up and larger datasets will better define the magnitude of PFS benefit and durability after treatment discontinuation. Second, while TEAEs decreased over time overall, the nature, reversibility, and long-term consequences of specific adverse events (particularly reproductive endocrine effects) require continued surveillance and reporting.
Generalizability to special populations (for example, adolescents, pregnant patients, or those with significant comorbidity) is limited by the trial population characteristics. Finally, optimal treatment duration, strategies for dose modification, and sequencing relative to other systemic agents or local therapies have not been established and should be the focus of pragmatic studies and clinical guidelines to aid shared decision-making.
Clinical Implications and Practical Recommendations
For clinicians caring for adults with progressing desmoid tumors, the long-term DeFi results suggest that nirogacestat is a potent, durable oral option that can produce sustained symptom and tumor control. Practical considerations for implementation include baseline counseling on likely adverse events, proactive monitoring (including consideration of reproductive counseling for patients of childbearing potential), and individualized assessment of treatment goals (symptom palliation, tumor shrinkage to facilitate function-preserving surgery, long-term disease control).
Given the potential for continued tumor regression with extended treatment, clinicians should weigh the potential benefits of prolonged therapy against cumulative toxicity and patient preferences. Multidisciplinary care—involving oncology, surgery, radiology, physiotherapy, and reproductive specialists as indicated—remains essential for optimal management.
Conclusion
Extended follow-up from the DeFi phase III trial confirms that continuous nirogacestat provides durable objective responses, ongoing tumor shrinkage, and sustained patient-reported benefits in adults with progressive desmoid tumors, with a safety profile that becomes more favorable over time for most patients. These data support nirogacestat as an important systemic option in the treatment algorithm for progressive, symptomatic desmoid tumors, while underscoring the need for continued long-term surveillance of adverse events, clarification of optimal treatment duration, and investigation of sequencing strategies with other therapies.
Funding and ClinicalTrials.gov
The long-term analysis and its detailed funding disclosures are presented in the primary publication: Ratan R et al., J Clin Oncol. 2025 (see reference below). The DeFi trial is registered at ClinicalTrials.gov under identifier NCT03785964.
References
1) Ratan R, Kasper B, Alcindor T, Schöffski P, van der Graaf WTA, Federman N, Bui NQ, D’Amato G, Riedel RF, Attia S, Chawla S, Lim A, Tumminello B, Oton AB, Chu Y, Zhou S, Gounder M. Efficacy and Safety of Long-Term Continuous Nirogacestat Treatment in Adults With Desmoid Tumors: Results From the DeFi Trial. J Clin Oncol. 2025 Dec;43(34):3646-3651. doi: 10.1200/JCO-25-00582 . Epub 2025 Oct 20. PMID: 41115259 ; PMCID: PMC12634144 .
